(a) Field of the Invention
The present invention relates to a delivery system of nucleic acid comprising a cationic polymer conjugate prepared from hyaluronic acid or its derivative and polyethyleneimine, and more specifically, a composition for delivering a nucleic acid into mammalian cell comprising a complex of a cationic polymer conjugate prepared from hyaluronic acid or its derivative and polyethyleneimine, and nucleic acid bound to the cationic polymer conjugate through an electrostatic interaction.
(b) Description of the Related Art
siRNA, antisense oligonucleic acids, plasmid deoxyribonucleic acid, and etc. are recently very important in the medicinal industrial fields as a nucleic acid drug. To develop the nucleic acid as a medicine, the most important problem is efficient delivery of the nucleic acid into cell or tissue. To deliver the nucleic acid into cell, viral vector or non-viral vectors, such as a polymer and nanoparticle, have been researched. The viral vector is advantageous in higher efficiency of the gene delivery than non-viral vector. However, the viral vector has a problem of safety in use, and thus has very limiting range for being used for human.
Non-viral vector has been developed as an alternative for viral vector. Cationic polymer, polyethyleneimine (PEI) forms colloidal particle with nucleic acid having negative charge, and has a pH buffering capacity in lysosome. Thus, it has been reported that PEI transfers plasmid deoxyribonucleic acid into various cells [Godbey et al., J. Controlled Release 60 (1999) 149-160]. However, there are many researches to solve the problems of the gene transfer efficiency into cell and cytotoxicity. Gosselin et al. reported that crosslinked PEI having low molecular was used for gene transfer [M. A. Gosselin M. A. et al., Bioconjugate Chem. 12 (2001) 989-994]. The PEI having low molecular weight shows low cytotoxicity, but lower gene expression efficiency than PEI 25K.
To reduce the cytotoxicity of PEI, PEI has been modified with dextran sulfate, human serum albumin, polyethylene glycol and etc., but all modified PEI show lower gene delivery efficiency than unmodified PEI. According to Erbacher et al., when a complex of nucleotide and the modified PEI with polyethylene glycol is administered to in vivo, spatial stability effect of “brush” layer, caused by the polyethylene glycol part on complex surface, increases circulation time of nucleotide in blood flow, but also lower delivering efficiency than unmodified PEI [Erbacher P. et al., J. Gene. Med. 1 (1999) 210-222].
Accordingly, the technology being capable of efficiently delivering oligonucleic acids such as siRNA and an antisense oligonucleic acid with low cytotoxicity needs in the field.